About one in 10 infants born in the United States
are delivered preterm, prior to the 37th gestational week of pregnancy,
suggested the Centers for Disease Control and Prevention.
injury associated with preterm birth - including white matter injury -
can have long-term cognitive and behavioral consequences, with more than
50% of infants who survive prematurity needing special
education, behavioral intervention and pharmacological treatment.
‘The sirtuin protein Sirt1 plays a crucial role in regenerating glial cells from endogenous progenitor cells after hypoxia-related brain injury suffered by preemies.’
Developing brains in newborns have a sizable pool of a certain type
of immature progenitor cell that can be expanded and induced to replace
cells lost to brain injury.
In a pre-clinical model of premature brain
injury, the sirtuin protein Sirt1 plays a crucial role in regenerating
glial cells from endogenous progenitor cells after hypoxia-related brain
injury suffered by preemies, a research team led by Children's National
Health System reports in Nature Communications
"It is not a cure. But, in order to regenerate the white matter that
is lost or damaged, the first steps are to identify endogenous cells
capable of regenerating lost cells and then to expand their pool. The
glial progenitor cells represent 4-5% of total brain cells,"
says Vittorio Gallo, Director of the Center for Neuroscience
Research at Children's National, and senior author of the study.
sizable pool, considering that the brain is made up of billions of
cells. The advantage is that these progenitor cells are already there,
with no requirement to slip them through the blood-brain barrier.
Eventually they will differentiate into oligodendrocyte cells in white
matter, mature glia, and that's exactly what we want them to do."
The study team identified Sirt1 as a novel, major regulator of basal
oligodendrocyte progenitor cell (OPC) proliferation and regeneration in
response to hypoxia in neonatal white matter, Gallo and co-authors
"We demonstrate that Sirt1 deacetylates and activates Cdk2, a
kinase which controls OPC expansion. We also elucidate the mechanism by
which Sirt1 targets other individual members of the Cdk2 signaling
pathway, by regulating their deacetylation, complex formation and E2F1
release, molecular events which drive Cdk2-mediated OPC proliferation,"
says Li-Jin Chew, Research Associate Professor at Children's
Center for Neuroscience Research and a study co-author.
Hypoxia-induced brain injury in neonates initiates spontaneous
amplification of progenitor cells but also causes a deficiency of mature
oligodendrocytes. Inhibiting Sirt1 expression in vitro and in vivo
showed that loss of its deacetylase activity prevents OPC proliferation
in hypoxia while promoting oligodendrocyte maturation - which
underscores the importance of Sirt1 activity in maintaining the delicate
balance between these two processes.
The tantalizing findings - the result of four years of research work
in mouse models of neonatal hypoxia - hint at the prospect of lessening
the severity of developmental delays experienced by the majority of
preemies, Gallo adds.
Time is of the essence, since Sirt1 plays a beneficial role at a
certain place (white matter) and at a specific time (while the immature
brain continues to develop). "We see maximal Sirt1 expression and
activity within the first week after neonatal brain injury. There is a
very narrow window in which to harness the stimulus that amplifies the
progenitor cell population and target this particular molecule for
repair," he says.
Sirt1, a nicotinamide adenine dinucleotide-dependent class III
histone deacetylase, is known to be involved in normal cell development,
aging, inflammatory responses, energy metabolism and calorie
restriction, the study team reports. Its activity can be modulated by
sirtinol, an off-the-shelf drug that inhibits sirtuin proteins. The
finding points to the potential for therapeutic interventions for
diffuse white matter injury in neonates.
Next, the research team aims to study these processes in a large
animal model whose brains are structurally, anatomically and
metabolically similar to the human brain.
"Ideally, we want to be able to promote the timely regeneration of
cells that are lost by designing strategies for interventions that
synchronize these cellular events to a common and successful end," Gallo